PROJECT SUMMARY The overarching goal of the proposed research is to improve our understanding of the neurobiological basis of autism spectrum disorders (ASDs). In this project we will analyze sequencing data collected from tens of thousands of individuals with and without ASD, and examine the rate at which gene knockouts (mutations that disrupt both functional copies of a gene) occur. Gene knockouts, while rare, can reveal critical biological pathways that teach us about the basis of disease. We will compare and contrast rates and patterns of these knockouts between cases and controls, study the effect of gender, and relate these patterns to the known preponderance of males with ASD. We will also use this data to generate a catalog of specific genes that are knocked out more frequently in individuals with ASD than in the general population. Finally, from this catalog, the strongest gene candidates will be chosen for neurobiological functional studies, to provide insight into how dysfunction may alter brain development and plasticity in autistic individuals.